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Rec Cell Biology & its Disorders
Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results
Farid Boulad,1,2 Tsiporah Shore,3 Koen van Besien,3 Caterina Minniti,4 Mihaela Barbu-Stevanovic,5 Sylvie Wiener Fedus,6 Fabiana Perna,2 June Greenberg,7 Danielle Guarneri,7 Vijay Nandi,5 Audrey Mauguen,8 Karina Yazdanbakhsh,5 Michel Sadelain2 and Patricia A. Shi4,5
1Department of Pediatrics, BMT Service, Memorial Sloan Kettering Cancer Center, New York; 2Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York; 3Bone Marrow and Hematopoietic Stem Cell Transplant Program, Weill Cornell Medicine/ New York Presbyterian Hospital, New York; 4Sickle Cell Program, Division of Hematology, Albert Einstein College of Medicine, Bronx; 5Lindsley F. Kimball Research Institute, New York Blood Center, NY; 6Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York; 7Division of Hematology and Oncology, Weill Cornell Medicine /New York Presbyterian Hospital, NY and 8Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
ABSTRACT
Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduc- tion or gene editing. We therefore performed a phase I dose-esca- lation study of the hematopoietic progenitor cell mobilizing agent pler- ixafor to evaluate the efficacy and safety of standard dosing on periph- eral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerix- afor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administra- tion did not induce significant increases in the fraction of activated neu- trophils, monocytes, or platelets. However, increased neutrophils posi- tive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administra- tion. Clinicaltrials.gov identifier: NCT02193191.
Introduction
Autologous gene therapy holds considerable promise for the treatment of patients with sickle cell disease (SCD).1,2 However, its successful application requires an adequate number of hematopoietic progenitor cells (HPC) for gene transfer or gene editing.3 Steady-state bone marrow has been the historical source of HPC for SCD gene therapy, but its harvest requires general anesthesia and has been complicated in current gene therapy trials by the need for repeated bone mar- row harvests and a high rate of adverse events.4 Granulocyte colony-stimulating factor (G-CSF) is a standard method of mobilizing HPC but its use in SCD patients has been associated with vaso-occlusive complications and even death.5 The mechanism of action of G-CSF involves activation of neutrophils,6 and is also asso- ciated with endothelial cell, platelet, and coagulation system activation,7-11 all of which may play a crucial role in sickle cell vaso-occlusion.12
Haematologica 2018 Volume 103(5):770-777
In contrast to G-CSF, plerixafor is a bicyclam reversible small molecule inhibitor
Correspondence:
pshi@nybc.org
Received: December 22, 2017. Accepted: January 23, 2018. Pre-published: February 1, 2018.
doi:10.3324/haematol.2017.187047
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/770
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